Intramolecular Diels-Alder cycloaddition/rearrangement cascade of an amidofuran derivative for the synthesis of (±)-minfiensine

Article abstract of DOI:10.1021/ol201320v

An efficient synthesis of (±)-minfiensine has been accomplished employing an intramolecular Diels-Alder cycloaddition/rearrangement cascade of an amidofuran derivative. Thermal reorganization of the initially formed [4 + 2]-cycloadduct affords the critica

Full text of DOI:10.1021/ol201320v

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3767–3769
Intramolecular DielsꢀAlder
Cycloaddition/Rearrangement Cascade of
an Amidofuran Derivative for the
Synthesis of (()-Minfiensine
Gang Li and Albert Padwa*
Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States
chemap@emory.edu
Received May 16, 2011
ABSTRACT
An efficient synthesis of (()-minfiensine has been accomplished employing an intramolecular DielsꢀAlder cycloaddition/rearrangement cascade
of an amidofuran derivative. Thermal reorganization of the initially formed [4 þ 2]-cycloadduct affords the critical tetrahydroiminoethanocarbazole
skeleton of the alkaloid in high yield.
In 1989, the indole alkaloid minfiensine (1) containing
the 1,2,3,4-tetrahydro-9a,4a-iminoethanocarbazole core (2)
was isolated from the African plant Strychnos minfiensis by
Massiot and co-workers (Figure 1).1 Since Overman’s inau-
gural synthesis of minfiensine,2 this structure and related
akuammiline indole alkaloids have continued to attract syn-
thetic interest due to their unusual polycyclic architecture and
diverse biological activity.3ꢀ6 In 2008, Qin and co-workers
also accomplished the total synthesis of (()-minfiensine (1) in
Figure 1. Core skeleton of akuammiline alkaloids.
18 steps proceeding in a 0.4% overall yield by making use of
an R-diazoketone cyclopropanation, ring-opening, and ring-
closure reaction starting from a N-tosyl tetrahydrocarboline
ester.7 Later, the MacMillan group reported a more efficient
synthetic route to this alkaloid using a cascade organocatalysis
sequence to build the central tetracyclic pyrroloindoline
framework and obtaining (þ)-minfiensine in 9 steps and
(1) Massiot, G.; Thepenier, P.; Jacquier, M. J.; Men-Oliver, L.;
Delaude, C. Heterocycles 1989, 29, 1435.
21% overall yield from commercial materials.8
(2) (a) Dounay, A. B.; Overman, L. E.; Wrobleski, A. D. J. Am.
Chem. Soc. 2005, 127, 10186. (b) Dounay, A. B.; Humphreys, P. G.;
Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2008, 130, 5368.
Our retrosynthetic analysis of minfiensine (1) is outlined
in Scheme 1. The synthetic plan that we initially had in
mind involved generation of the E-ring of minfiensine by a
palladium catalyzed intramolecular enolate coupling9 of
(3) Ramirez, A.; Garcıa-Rubio, S. Curr. Med. Chem. 2003, 10, 1891.
´
(4) (a) Manohar, H.; Ramaseshan, S. Tetrahedron Lett. 1961, 22, 814.
(b) Goodson, J. A. J. Chem. Soc. 1932, 134, 2626. (c) Goodson, J. A.;
Henry, T. A. J. Chem. Soc. 1925, 127, 1640.
(5) (a) Morfaux, A. M.; Mouton, P.; Massiot, G.; LeMen-Oliver, L.
Phytochemistry 1992, 31, 1079. (b) Mokry, J.; Dubravkova, L.; Sefcovic,
P. Experientia 1962, 18, 564.
(6) Proksa, B.; Uhrin, D.; Grossmann, E.; Voticky, Z. Planta Med.
1987, 53, 120.
(8) Jones, S. B.; Simmons, B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2009, 131, 13606.
ꢀ
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(9) (a) Sole, D.; Peidro, E.; Bonjoch, J. Org. Lett. 2000, 2, 2225.
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(b) Sole, D.; Diaba, J.; Bonjoch, J. J. Org. Chem. 2003, 68, 5746.
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(c) Bonjoch, J.; Diaba, F.; Puigbo, G.; Peidro, E.; Sole, D. Tetrahedron
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(7) Shen, L.; Zhang, M.; Wu, Y.; Qin, Y. Angew. Chem., Int. Ed.
2008, 47, 3618.
Lett. 2003, 44, 8387. (d) Sole, D.; Urbaneja, X.; Bonjoch, J. Org. Lett.
2005, 7, 5461.
r
10.1021/ol201320v
2011 American Chemical Society
Published on Web 06/22/2011

prudent to first explore a model system to test the validity
of this approach. With this in mind, furanyl carbamate 12
was prepared by application of a BuchwaldꢀHartwig
copper catalyzed amidation reaction.13 The keto group
present in the resulting cross coupled product 11 derived
from 9 and 10 was converted into the corresponding
carbamate 12 using standard methodology.14
Scheme 1
Scheme 2
the tethered vinyl iodide 3 as was recently carried out in
our synthesis of strychnine.10 Our first attempt to synthe-
size the required tetracyclic precursor 4 was based on the
assumption that 4 would be formed by protonation of the
3a-aryl-2,3,3a,4-tetrahydro-1H-indol-5(6H)-one 5. This
compound would, in turn, be generated by an IMDAF
cycloaddition reaction of amidofuran 6 followed by a
subsequent rearrangement of the initially formed [4 þ 2]-
oxabicyclic adduct.11 However, all of our efforts to form 5
from the thermolysis of furan 6 only resulted in recovered
starting material. Apparently, the presence of a substituent
group in the ortho position of the aromatic ring causes an
unfavorable steric interaction with the furan ring in the
reactive “DielsꢀAlder conformation”12 thereby diminish-
ing the overall rate of the IMDAF cycloaddition of 6.
Having been thwarted in attempts to use amidofuran 6
as a precursor to tetracycle 4, we decided that the simplest
adjustment to our IMDAF approach would be to investi-
gate the thermolysis of the related aminofuran 8. As we
were unsure as to whether the critical cycloaddition/
rearrangement cascade would occur with 8, we felt it
We were pleased to find that heating a sample of furanyl
carbamate 12a (or 12b) gave rise to the dihydro-2H-
carbazolone 13a (or 13b) in ca. 80% yield (Scheme 2)
thereby providing a promising prognosis for the success of
our IMDAF cycloaddition approach toward minfiensine.
Our synthesis of the alkaloid minfiensine began with
commercially available boronate 14 which was smoothly
transformed through a SuzukiꢀMiyaura cross-coupling
reaction with vinyl iodide 15 into the o-styryl substituted
amide 16 in 63% yield (Scheme 3). Conversion of
the alcohol into the corresponding mesylate 17 followed
by reaction with allyl amine provided the expected second-
ary amine 18 (R = H) which was easily converted to
the corresponding t-Boc carbamate 19 (72%). After a
thorough screening of various catalytic systems (including
several Pd(0) catalysts and bis-phosphine ligand combina-
tions), we found that Buchwald’s CuI catalytic system gave
the most consistent and promising results.15 Thus, heating
a mixture of 19 together with catalytic copper(I)-thiophene-
2-carboxylate (CuTC) and Cs2CO3 in toluene at 90 °C
produced the DielsꢀAlder cycloadduct 21 derived from a
subsequent [4 þ 2]-cycloaddition of the expected cross-
coupled product (i.e., 8). Further heating of 21 at 120 °C
afforded 23 (81%) obtained from the sequential ring-
openingꢀdeprotonation cascade.12 A related sequence of
reactions occurred when the simpler NH-amine 18 was
(10) (a) Zhang, H.; Boonsombat, J.; Padwa, A. Org. Lett. 2007, 9,
279. (b) Boonsombat, J.; Zhang, H.; Chughtai, M. J.; Hartung, J;
Padwa, A. J. Org. Chem. 2008, 73, 3539.
(11) Bobeck, D. R.; France, S.; Leverett, C. A.; Sanchez-Cantalejo,
F.; Padwa, A. Tetrahedron Lett. 2009, 50, 3145.
(12) (a) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J. Org.
Chem. 1997, 62, 4088. (b) Padwa, A.; Brodney, M. A.; Dimitroff, M.
J. Org. Chem. 1998, 63, 5304. (c) Padwa, A.; Brodney, M. A.; Satake, K.;
Straub, C. S. J. Org. Chem. 1999, 64, 4617.
(13) (a) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144.
(b) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2047. (c) For several
methods to synthesize 2-amido substituted furans, see: Padwa, A.;
Crawford, K. R.; Rashatasakhan, P.; Rose, M. J. Org. Chem. 2003,
68, 2609.
(14) Pine, S. Org. React. 1993, 43, 2.
(15) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 7421.
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Org. Lett., Vol. 13, No. 15, 2011

Scheme 3
Scheme 4
cross-coupling reaction with tri-n-butylstannylmethanol19
furnished pentacycle 29. Finally, removal of the acetyl
group with hydrazine led to the isolation of (()-minfiensine
in 78% yield.
In summary, an efficient synthesis of (()-minfiensine
has been achieved. A distinctive feature of the synthesis is
the use of an intramolecular DielsꢀAlder cycloaddition/
rearrangement cascade of an amidofuran derivative. The
synthetic sequence starts with an easily prepared o-styryl
substituted amide by a SuzukiꢀMiyaura cross-coupling
reaction. A subsequent BuchwaldꢀHartwig amidation
leads to a transient furanyl amide which undergoes ready
[4 þ 2]-cycloaddition across the tethered p-bond. Thermal
reorganization of the resulting cycloadduct affords the
critical tetrahydroiminoethanocarbazole skeleton of the
alkaloid in high yield. The functionality present in the
pentacyclic skeleton allowed for the final elaboration to
(()-minfiensine.
cross-coupled with 2-bromofuran using CuTC as the
catalyst. In this case, cycloadduct 20 was obtained in
82% yield. When 20 was heated in toluene at 120 °C in
the presence of catalytic MgI2, the only product isolated
in 60% yield corresponded to tetracycle 24 presumably
derived from an acid catalyzed cyclization of 22. Removal
of the N-allyl group from 24 was easily realized with
Pd(PPh3)4 and N,N-dimethylbarbituric acid using a pro-
16
ꢀ
cedure developed by Guibe and co-workers in 85% yield.
The required vinyl iodide cyclization precursor 26 was then
secured in 67% yield by reaction of secondary amine
25 with Z-2-iodo-2-butenyl mesylate17 employing K2CO3
as the base in acetonitrile at 70 °C. With tetracyclic
iodoketone 26 in hand, we turned toward the formation
of minfiensine by a palladium-catalyzed intramolecular
enolate/vinyl iodide coupling (Scheme 4).9,18 The reaction
was carried out in methanol using 10 mol % of PdCl2-
(dppf) and 4 equiv of K2CO3 at 70 °C which afforded the
expected pentacyclic ketone 27 in 67% yield. Straight-
forward conversion of 27 to the corresponding enol
triflate 28 using Comins’ reagent followed by a Stille
Acknowledgment. We appreciate the financial support
provided by the National Science Foundation (CHE-
1057350).
Supporting Information Available. Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
ꢀ
(16) Garro-Helion, F.; Merzouk, A.; Guibe, F. J. Org. Chem. 1993,
58, 6109.
(17) Wanner, M. J.; Boots, R. N. A.; Eradus, B.; de Gelder, R.;
Van Maarseveen, J. H.; Hiemstra, H. Org. Lett. 2009, 11, 2579.
(18) Zhang, H.; Boonsombat, J.; Padwa, A. Org. Lett. 2007, 9, 279.
(19) Danheiser, R. L.; Romines, K. R.; Koyama, H.; Gee, S. K.;
Johnson, C. R; Medich, J. R. Org. Synth. 1993, 71, 133.
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